Risks Increase on Episodic Antiretroviral Therapy

In the study, the investigators used two predetermined levels of CD4+ T cells, the primary immune cell targeted by HIV, to guide them in respectively suspending or restarting the study participants on antiretroviral therapy. The trial involved 318 clinical sites in 33 countries and is known as Strategies for Management of Anti-Retroviral Therapies, or SMART.

SMART was designed to determine which of two different HIV treatment strategies would result in greater overall clinical benefit. Volunteers with chronic HIV infection—nearly all of whom had taken antiretroviral therapy (ART)—were assigned at random to one of two groups. In the "viral suppression" group, with 2,752 participants, ART was taken on an ongoing basis to suppress HIV viral load; in the "drug conservation" group, with 2,720 volunteers, participants received episodic ART in an effort to reduce drug side effects and preserve treatment options.

In the latter group, ART was suspended whenever CD4+ counts were above 350 cells per cubic millimeter (mm3) and ART was started only when levels of CD4+ cells dropped below 250 cells/mm3. The CD4+ count thresholds for stopping and starting ART were chosen based on previously reported associations between CD4+ counts and risks of opportunistic diseases and death.

In early 2006, National Institute of Allergy and Infectious Diseases (NIAID) announced that enrolment into the trial had been halted after review of the interim data by an independent data and safety monitoring board (DSMB) found that those participants receiving episodic therapy had a significantly increased risk of disease progression. "Disease progression" was defined as the development of an opportunistic disease (AIDS) or death from any cause.

At the time the trial was stopped, 120 participants in the drug conservation group compared with 47 on continuous antiretroviral therapy had developed disease progression. The difference represents a 2.6-fold increased risk for those receiving episodic treatment. Notably, the drug conservation group had significantly more major adverse events, specifically, cardiovascular, kidney and liver disease, complications previously associated with ART. The study investigators had hoped that these complications would be seen less frequently in those trial volunteers receiving less drug.